Myelin is an electrically insulating material which encases the axons of neurons forming a layer known as the myelin sheath. The primary purpose of myelin is to increase the speed at which nerve impulses propagate down the neural axon. By increasing the electrical resistance across the cell membrane, myelin helps prevent the electrical current from leaving the axon.
Neural demyelination is a condition characterized by a reduction of myelin protein in the nervous system, and is the basis for many neurodegenerative autoimmune diseases such as multiple sclerosis, experimental autoimmune encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, progressive multifocal leukoencephalopathy, transverse myelitis, Guillain-Barré Syndrome, central pontine myelinosis, Alzheimer's Disease, progressive supenuclear palsy, multifocual motor neuropathy, and leukodystrophies such as Adrenoleukodystrophy (ALD), Alexander's Disease, Canavan Disease, Krabbe Disease, Metachromatic Leukodystrophy (MLD), Pelizaeus-Merzbacher Disease, Refsum Disease, Cockayne Syndrome, Van der Knapp Syndrome, and Zellweger Syndrome.
In particular, multiple sclerosis is the most common demyelinating disease, causing disability in many young adults. Because of demyelination and scarring, multiple sclerosis affects the ability of nerve cells in the brain and spinal cord to communicate with each other. As such, a person suffering from multiple sclerosis can exhibit a variety of neurological symptoms, including changes in sensation such as loss of sensitivity or tingling, muscle weakness, loss of coordination and paralysis. The disease generally occurs in two stages, a relapsing stage and a chronic progressive phase.
Current treatments for multiple sclerosis include anti-inflammatory and immuno-modulatory approaches. However, both are only partially effective in the relapsing stage of the disease, and little to no effect on the secondary progressive phase of the disease. Recently, estrogen receptor-β modulators have been shown to slow such neurodegeneration. Carswell, H. V. O. et al., AJP-Heart Circ. Physiol., 2004, vol. 287, 1501-04; Crawford, D. K. et al., Brain, 2010, vol. 133, 2999-3016; Donzelli, A. et al., J. Pharmacol. Sci., 2010, vol. 114, 158-167.
Therefore, a need for an effective treatment for demyelinating diseases remains. Specifically, a compound which stimulates endogenous myelination and spares axon degeneration is preferred.